Alzheimer's disease (AD) is a neurodegenerative syndrome generally linked with ageing which leads patients to a progressive deterioration of their cognitive and behavioural functions. The great majority of cases of AD has causes that are currently substantially unknown. Also for this reason, today there are still no therapeutic treatments able to halt the progression of the disease, even though some drugs have recently been put on the market, aimed especially at the control of the cognitive symptoms. These drugs—Tacrine (Cognex®), Doenpezil (Aricept®) Rivastigime (Exelon®) and Galantamine (Reminyl®)—share the same action mechanism, which consists of the inhibition of acetylcholinesterase (AChE).
Although the strengthening of cholinergic neurotransmission through the inhibition of AChE is a useful approach to the treatment of cognitive symptoms associated with AD, it has recently been proposed that the loss of neurones and the consequent appearance of cognitive symptoms are the result of a cascade of biochemical events linked with the overproduction of β-amyloid protein (Aβ) in certain cerebral areas. The Aβ peptide is obtained from the proteolysis of APP, a type I membrane glycoprotein; the peptide sequence is located partly in the extracellular domain and partly in the transmembrane in pathological conditions, the APP is processed by two proteolytic enzymes, β- and γ-secretase. Due to the action of β-secretase (BACE), a membrane aspartil protease, the release of a shorter fragment (APPβ) from the membrane is obtained, while the C-terminal portion of 99 amino acids remains anchored to the membrane. The C99 in turn may be processed by another enzyme γ-secretase, giving rise to the Aβ peptide. This protein tends to aggregate, forming extracellular deposits, which give rise to the typical lesions found in the brain of AD patients: senile plaques. The presence of these plaques produces responses of an inflammatory and oxidative type in the surrounding tissue, triggering a chain of toxic events, including an increase of the phosphorylation of tau protein, due to the activation of enzymes of inflammation and to the formation of oxygenated radical species. The progression of neurodegeneration derives from the impossibility of controlling the spread of these harmful effects. It is therefore necessary to discover pharmacological instruments that are able to act as far upstream as possible in the neurodegenerative cascade. Moreover, it is important to stress that there are other pathologies besides AD characterised by Aβ deposits. These pathologies include: Down's syndrome, hereditary cerebral haemorrhage associated with amyloidosis of the “Dutch type”, amyloidosis associated with chronic inflammations, amyloidosis associated with multiple myelomas and other dyscrasias of the B lymphoid haematic cells, amyloidosis associated with type II diabetes, amyloidosis associated with diseases derived from pryons such as Creutzfeldt-Jakob's disease, the Gerstmann-Straussler syndrome, Kuru disease and scrapie in sheep (WO 02/00603).
In the field of pharmaceutical products for the treatment of AD, the patent application PCT/IT03/00227 led to the identification of a new family of 2,5-bis-diamino-[1,4]benzoquinonic derivatives which have demonstrated, among other properties, relatively high activities for the treatment of AD in mammals.
From the above it is clear that there is still a considerable need to make new medicaments available for the treatment of AD.